Quantification of Tau Protein Lysine Methylation in Aging and Alzheimer's Disease

Carol J. Huseby, Claire N. Hoffman, Grace L. Cooper, Jean Christophe Cocuron, Ana P. Alonso, Stefani N. Thomas, Austin J. Yang, Jeff Kuret

Research output: Contribution to journalArticle

Abstract

Tau is a microtubule-associated protein that normally interacts in monomeric form with the neuronal cytoskeleton. In Alzheimer's disease, however, it aggregates to form the structural component of neurofibrillary lesions. The transformation is controlled in part by age- and disease-associated post-translational modifications. Recently we reported that tau isolated from cognitively normal human brain was methylated on lysine residues, and that high-stoichiometry methylation depressed tau aggregation propensity in vitro. However, whether methylation stoichiometry reached levels needed to influence aggregation propensity in human brain was unknown. Here we address this problem using liquid chromatography-tandem mass spectrometry approaches and human-derived tau samples. Results revealed that lysine methylation was present in soluble tau isolated from cognitively normal elderly cases at multiple sites that only partially overlapped with the distributions reported for cognitively normal middle aged and AD cohorts, and that the quality of methylation shifted from predominantly dimethyl-lysine to monomethyl-lysine with aging and disease. However, bulk mol methylation/mol tau stoichiometries never exceeded 1 mol methyl group/mol tau protein. We conclude that lysine methylation is a physiological post-translational modification of tau protein that changes qualitatively with aging and disease, and that pharmacological elevation of tau methylation may provide a means for protecting against pathological tau aggregation.

Original languageEnglish (US)
Pages (from-to)979-991
Number of pages13
JournalJournal of Alzheimer's Disease
Volume71
Issue number3
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

Fingerprint

tau Proteins
Methylation
Lysine
Alzheimer Disease
Post Translational Protein Processing
Microtubule-Associated Proteins
Brain
Tandem Mass Spectrometry
Cytoskeleton
Liquid Chromatography
Pharmacology

Keywords

  • Aging
  • Alzheimer's disease
  • mass spectrometry
  • methylation
  • phosphorylation
  • post-translational modification
  • tau protein

PubMed: MeSH publication types

  • Journal Article

Cite this

Huseby, C. J., Hoffman, C. N., Cooper, G. L., Cocuron, J. C., Alonso, A. P., Thomas, S. N., ... Kuret, J. (2019). Quantification of Tau Protein Lysine Methylation in Aging and Alzheimer's Disease. Journal of Alzheimer's Disease, 71(3), 979-991. https://doi.org/10.3233/JAD-190604

Quantification of Tau Protein Lysine Methylation in Aging and Alzheimer's Disease. / Huseby, Carol J.; Hoffman, Claire N.; Cooper, Grace L.; Cocuron, Jean Christophe; Alonso, Ana P.; Thomas, Stefani N.; Yang, Austin J.; Kuret, Jeff.

In: Journal of Alzheimer's Disease, Vol. 71, No. 3, 01.01.2019, p. 979-991.

Research output: Contribution to journalArticle

Huseby, CJ, Hoffman, CN, Cooper, GL, Cocuron, JC, Alonso, AP, Thomas, SN, Yang, AJ & Kuret, J 2019, 'Quantification of Tau Protein Lysine Methylation in Aging and Alzheimer's Disease', Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 979-991. https://doi.org/10.3233/JAD-190604
Huseby, Carol J. ; Hoffman, Claire N. ; Cooper, Grace L. ; Cocuron, Jean Christophe ; Alonso, Ana P. ; Thomas, Stefani N. ; Yang, Austin J. ; Kuret, Jeff. / Quantification of Tau Protein Lysine Methylation in Aging and Alzheimer's Disease. In: Journal of Alzheimer's Disease. 2019 ; Vol. 71, No. 3. pp. 979-991.
@article{e7cdcda12a4b4489b23f6b14a7c8f7be,
title = "Quantification of Tau Protein Lysine Methylation in Aging and Alzheimer's Disease",
abstract = "Tau is a microtubule-associated protein that normally interacts in monomeric form with the neuronal cytoskeleton. In Alzheimer's disease, however, it aggregates to form the structural component of neurofibrillary lesions. The transformation is controlled in part by age- and disease-associated post-translational modifications. Recently we reported that tau isolated from cognitively normal human brain was methylated on lysine residues, and that high-stoichiometry methylation depressed tau aggregation propensity in vitro. However, whether methylation stoichiometry reached levels needed to influence aggregation propensity in human brain was unknown. Here we address this problem using liquid chromatography-tandem mass spectrometry approaches and human-derived tau samples. Results revealed that lysine methylation was present in soluble tau isolated from cognitively normal elderly cases at multiple sites that only partially overlapped with the distributions reported for cognitively normal middle aged and AD cohorts, and that the quality of methylation shifted from predominantly dimethyl-lysine to monomethyl-lysine with aging and disease. However, bulk mol methylation/mol tau stoichiometries never exceeded 1 mol methyl group/mol tau protein. We conclude that lysine methylation is a physiological post-translational modification of tau protein that changes qualitatively with aging and disease, and that pharmacological elevation of tau methylation may provide a means for protecting against pathological tau aggregation.",
keywords = "Aging, Alzheimer's disease, mass spectrometry, methylation, phosphorylation, post-translational modification, tau protein",
author = "Huseby, {Carol J.} and Hoffman, {Claire N.} and Cooper, {Grace L.} and Cocuron, {Jean Christophe} and Alonso, {Ana P.} and Thomas, {Stefani N.} and Yang, {Austin J.} and Jeff Kuret",
year = "2019",
month = "1",
day = "1",
doi = "10.3233/JAD-190604",
language = "English (US)",
volume = "71",
pages = "979--991",
journal = "Journal of Alzheimer's Disease",
issn = "1387-2877",
publisher = "IOS Press",
number = "3",

}

TY - JOUR

T1 - Quantification of Tau Protein Lysine Methylation in Aging and Alzheimer's Disease

AU - Huseby, Carol J.

AU - Hoffman, Claire N.

AU - Cooper, Grace L.

AU - Cocuron, Jean Christophe

AU - Alonso, Ana P.

AU - Thomas, Stefani N.

AU - Yang, Austin J.

AU - Kuret, Jeff

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Tau is a microtubule-associated protein that normally interacts in monomeric form with the neuronal cytoskeleton. In Alzheimer's disease, however, it aggregates to form the structural component of neurofibrillary lesions. The transformation is controlled in part by age- and disease-associated post-translational modifications. Recently we reported that tau isolated from cognitively normal human brain was methylated on lysine residues, and that high-stoichiometry methylation depressed tau aggregation propensity in vitro. However, whether methylation stoichiometry reached levels needed to influence aggregation propensity in human brain was unknown. Here we address this problem using liquid chromatography-tandem mass spectrometry approaches and human-derived tau samples. Results revealed that lysine methylation was present in soluble tau isolated from cognitively normal elderly cases at multiple sites that only partially overlapped with the distributions reported for cognitively normal middle aged and AD cohorts, and that the quality of methylation shifted from predominantly dimethyl-lysine to monomethyl-lysine with aging and disease. However, bulk mol methylation/mol tau stoichiometries never exceeded 1 mol methyl group/mol tau protein. We conclude that lysine methylation is a physiological post-translational modification of tau protein that changes qualitatively with aging and disease, and that pharmacological elevation of tau methylation may provide a means for protecting against pathological tau aggregation.

AB - Tau is a microtubule-associated protein that normally interacts in monomeric form with the neuronal cytoskeleton. In Alzheimer's disease, however, it aggregates to form the structural component of neurofibrillary lesions. The transformation is controlled in part by age- and disease-associated post-translational modifications. Recently we reported that tau isolated from cognitively normal human brain was methylated on lysine residues, and that high-stoichiometry methylation depressed tau aggregation propensity in vitro. However, whether methylation stoichiometry reached levels needed to influence aggregation propensity in human brain was unknown. Here we address this problem using liquid chromatography-tandem mass spectrometry approaches and human-derived tau samples. Results revealed that lysine methylation was present in soluble tau isolated from cognitively normal elderly cases at multiple sites that only partially overlapped with the distributions reported for cognitively normal middle aged and AD cohorts, and that the quality of methylation shifted from predominantly dimethyl-lysine to monomethyl-lysine with aging and disease. However, bulk mol methylation/mol tau stoichiometries never exceeded 1 mol methyl group/mol tau protein. We conclude that lysine methylation is a physiological post-translational modification of tau protein that changes qualitatively with aging and disease, and that pharmacological elevation of tau methylation may provide a means for protecting against pathological tau aggregation.

KW - Aging

KW - Alzheimer's disease

KW - mass spectrometry

KW - methylation

KW - phosphorylation

KW - post-translational modification

KW - tau protein

UR - http://www.scopus.com/inward/record.url?scp=85073090013&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85073090013&partnerID=8YFLogxK

U2 - 10.3233/JAD-190604

DO - 10.3233/JAD-190604

M3 - Article

C2 - 31450505

AN - SCOPUS:85073090013

VL - 71

SP - 979

EP - 991

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

SN - 1387-2877

IS - 3

ER -